Schizophrenia is a severe, mental disease that affects approximately 3 million Americans. There is now extensive evidence that cognitive symptoms (e.g., deficits in working memory and attention) are more important than other symptoms for functional recovery. Unfortunately, currently available antipsychotic drugs (APDs) do not provide adequate gains in cognitive impairment. However, recently synthesized brain penetrant analogs of the CNS peptide neurotensin have produced atypical antipsychotic drug-like effects in animal models, which is of interest because atypical antipsychotic drugs (e.g., risperidone) offer, albeit limited, improved cognitive efficacy for schizophrenia compared to typical antipsychotic drugs (e.g., haloperidol). Thus, stimulation of CNS neurotensin receptors has become to a viable pharmacologic strategy toward developing novel treatments for cognitive impairment in schizophrenia. Two such analogs will be studied in the proposed experiments: PD149163 and NT69L. Like endogenous neurotensin, which has extensive interactions with dopaminergic and cholinergic systems in brain areas important for cognitive functioning, including the prefrontal cortex and hippocampus, preliminary studies in our laboratory have found that NT69L elevates dopamine and acetylcholine levels in the prefrontal cortex. Moreover, we have also found that NT69L improves working memory function in a rodent novel object recognition task. The proposed studies will evaluate the effects of neurotensin analogs on cognitive functioning and elucidate the mechanisms mediating the atypical antipsychotic-like effects of neurotensin analogs through three specific aims. Specific Aim 1 will test the hypothesis that neurotensin analogs improve cognition by assessing the effects of neurotensin analogs on attention, reference memory, and working memory using standard behavioral models in rats. Specific Aims 2 and 3 will test the hypothesis that neurotensin analogs produce atypical antipsychotic-like effects on neurotransmission through a unique mechanism by 1.) comparing the effects of neurotensin analogs and atypical antipsychotic drugs on dopamine and acetylcholine efflux in the prefrontal cortex and hippocampus using microdialysis in rats and by 2.) determining the brain regions that mediate the effects of neurotensin analogs on dopamine and acetylcholine efflux in the prefrontal cortex and hippocampus using reverse microdialysis in rats. Thus, these experiments will illuminate a novel pharmacologic strategy for improving cognitive function in schizophrenia. Alleviating cognitive impairment in schizophrenia is expected to improve functional outcomes, such as gaining employment and conducting normal social interactions, and may therefore, reduce homelessness, hospitalization and the overall burden of this disease upon society. PUBLIC HEALTH RELEVANCE: The proposed experiments will illuminate a novel pharmacologic strategy for improving cognitive function in schizophrenia. Alleviating cognitive impairment in schizophrenia is expected to improve functional outcomes, such as gaining employment and conducting normal social interactions, and may therefore, reduce homelessness, hospitalization and the overall burden of this disease upon society.